This invention relates to the non-invasive measurement of the concentration of substances that absorb electromagnetic radiation, such as light or infrared radiation, in absorbing and turbid matrices, such as human or animal body tissue, using a probe beam of electromagnetic radiation. The invention is particularly applicable to glucose measurement in human tissue using near-infrared radiation. It is, however, generally applicable to measurements of the concentration of any species that absorbs electromagnetic radiation, especially in strongly absorbing and turbid matrices.
The infrared measurement methods known in the art are not well adapted to the problem of quantifying an analyte, such as glucose, dissolved in a strongly absorbing solvent, such as blood. The known methods include separate or directly alternating measurements at a “glucose” wavelength and at a “reference” wavelength, where glucose does not absorb, as well as differential wavelength modulation about a glucose absorption band (C. Dähne, D. Gross, European patent 0 160 768 and references therein). In the known methods, the signal is easily masked with the variations of the strong background presented by water and other constituents in the tissue and in the capillary blood flow.
The present invention is an improvement over U.S. Pat. No. 5,099,123, issued to Harjunmaa (hereafter, the “'123 patent”), which is incorporated herein in its entirety by reference. The balanced differential (or “optical bridge”) method disclosed in the '123 patent utilizes two wavelengths for target analyte concentration measurements. The first, or principal wavelength is chosen such to be highly absorbed in the target analyte. The second, or reference wavelength is chosen using a balancing process so that both wavelengths have substantially identical extinction coefficients in the background matrix. A radiation beam is generated that contains these two wavelengths in alternate succession at a suitable frequency. When the beam is properly balanced for the measurement, a sample detector, placed to measure radiation transmitted or reflected by the sample matrix that contains only a residual amount of the target analyte, will detect only a very small alternating component in the radiation, regardless of the thickness of the sample. When there is a relatively substantial amount of the target analyte in the sample matrix, however, the detector will detect a significant alternating signal synchronous with the wavelength alternation. This alternating signal is amplified and is then detected using a phase-sensitive detector (or lock-in amplifier). The optical bridge balancing process entails nulling out the alternating signal from the sample detector by systematically varying the relative intensities and/or wavelengths of the repetitive radiation periods. An auxiliary detector is also used to sample the combined beam before it enters the tissue in order to enhance the measurement stability. Although suitable for the purposes intended, the realization of the precautions taken to deal with the unavoidable differences in the spectral response between the auxiliary detector and the sample detector make the system somewhat complicated.
Subsequently in U.S. Pat. No. 5,178,142, (hereafter, the “'142 patent”), which is also incorporated by reference herein in its entirety, Harjunmaa et al. disclosed an improved method and apparatus in which the concentration measurement is performed using a two-wavelength alternating radiation probe beam which interacts with the tissue. One of the wavelengths is used as a reference wavelength, and the other is the principal wavelength. The reference wavelength is tunable to account for the expected variability of the background spectrum. After passing through the matrix that contains a given reference concentration of analyte, detected signals from the probe beam are balanced or nulled by tuning the variable wavelength beam over a range of frequencies. Next, the blood content of the sample is changed. The alternating component of the interacted probe beam is then detected. The amplitude of the alternating component of the signal given by the sample detector is proportional to the concentration of analyte or the difference from a preset reference analyte concentration.
Other related patents include U.S. Pat. Nos. 5,112,124; 5,137,023; 5,183,042; 5,277,181 and 5,372,135, each of which is incorporated by reference herein in its entirety.